M. Geissler et al., Intracellular retention of hepatitis B virus surface proteins reduces interleukin-2 augmentation after genetic immunizations, J VIROLOGY, 73(5), 1999, pp. 4284-4292
We have previously shown that hepatitis B virus (HBV) surface antigens (HBs
Ags) are highly immunogenic after genetic immunization. Compared to the sec
reted middle HBV surface proteins (MHBs) or small HBV surface proteins (SHB
s), the nonsecreted large HBV surface protein (LHBs), however, induced sign
ificantly weaker humoral and cellular immune responses that could not be au
gmented by genetic coimmunizations with cytokine expression plasmids, In or
der to understand the mechanisms underlying this phenomenon, we examined th
e effect of coimmunizations with an interleukin-2 (IL-2) DNA expression pla
smid on the immunogenicity at the B- and T-cell level of nonsecreted wild-t
ype LHBs, a secreted mutant LHBs, wild-type SHBs, and a nonsecreted mutant
SHBs. Coimmunizations of mice with plasmids encoding wild-type SHBs or the
secreted mutant LHBs and IL-2 increased anti-HBs responses, helper T-cell p
roliferative activity and cytotoxic T-lymphocyte killing. By contrast, coim
munizations of plasmids encoding wild-type LHBs or nonsecreted mutant SHBs
and IL-2 had no significant effects on immune responses, Interestingly, mic
e immunized with cytokine expression plasmids 14 days after the injection o
f the wild-type LHRs plasmid showed augmented immune responses compared to
animals simultaneously injected with both expression constructs. Anti-HBs r
esponses in mice injected with plasmids encoding secreted forms of HBsAgs w
ere detectable about 10 days earlier than those in mice immunized with plas
mids encoding nonsecreted forms of HBsAgs. Based on these observations, we
conclude that cytokines produced by DNA plasmids at the initial site of ant
igen presentation cannot augment LHBs specific immune responses because LHB
s is not produced at high enough levels or is not accessible for uptake by
antigen-presenting cells.